Intermittent hypoxia enhances the tumor programmed death ligand 1 expression in a mouse model of sleep apnea

Abstract

Background: As a hallmark of obstructive sleep apnea (OSA), intermittent hypoxia (IH) promotes tumor progress. The high expression of programmed death 1 and programmed death ligand 1 (PD-L1) in tumor leads to immune evasion and subsequently aggravates tumor progress. This study aims to determine the tumor PD-L1 expression under the IH condition.Methods: A total of 24 C57BL/6J mice were randomly assigned to the normoxia (control, CTL) group and the IH group. Mice in the IH group were subjected to the IH condition for 5 weeks. Lung cancer cells were injected into the flank of each mouse after 1 week of IH exposure. Tumor PD-L1 expression was detected by immunohistochemistry (IHC). Correlation between tumor weight, tumor volume, and expression of PD-L1 was analyzed.Results: Compared to the CTL group, mice in the IH group had a high PD-L1 expression. The IH can enhance the tumor PD-L1 expression. Tumor weight, volume, and HIF-1α levels were closely associated with the PD-L1 expression in the IH group, while dissimilar findings were observed in the CTL group. Conclusions:The IH enhances tumor PD-L1 expression in OSA mimicking mice. Additional studies are required to clarify the underlying mechanism.

Acute vs. Chronic vs. Cyclic Hypoxia: Their Differential Dynamics, Molecular Mechanisms, and Effects on Tumor Progression

“…Moreover, OSA patients showed increased population of MDSCs (myeloid cells capable of inhibiting innate and adaptive immune responses) with higher expression of RORC1 in their monocytes which promotes expansion of MDSC [146]. Higher expression of PD-L1 in tumor cells of IH (6% O 2 , 70 s hypoxia, 50 s reoxygenation, 8 h per day, for 5 weeks) treated OSA mice models of LLC cells has also been reported by Huang et al [147]. Similarly, Akbarpour et al showed that sleep fragmentation (SF) and IH (6% Fi O 2 , 90 s hypoxia, 90 s reoxygenation, 20 cycles per hour, 12 h per day till the tumor is palpable) increased tumor size and invasiveness, and IH reduced granzyme-B producing CD8+ cells in tumors of OSA TC1 mice model [148].…”

Sleep Apnoea Adverse Effects on Cancer: True, False, or Too Many Confounders?

“…Alternatively, some such confounding factors may be selectively introduced, to allow for studies of the interactions between, for example, IH and obesity [ 21 ], IH and ageing [ 22 ], and IH and menopause [ 23 ]. Table 1 presents a summary of the findings reported by 30 studies in animal models that investigated whether OSA boosts cancer malignant properties [ 13 , 16 , 17 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. The overall summary is reflected by the conclusion that both IH and SF increase tumorigenesis, tumour growth, invasion/metastasis, and angiogenesis.…”

“…Therefore, our current knowledge of the pathophysiology of cancer and OSA provides biological plausibility to the hypothesis that this sleep breathing disorder can initiate and/or aggravate malignancies. [13,17,20,22,[25][26][27][29][30][31][32]43,44] 3 [16,24,28] ↑ 13/13 ↑ 13/13…”

Sodium tanshinone IIA sulfonate attenuates tumor oxidative stress and enhances apoptosis in an intermittent hypoxia mouse model

“…As a novel hallmark of OSA, IH induces oxidative stress, systemic inflammation [13]. Tumor progression was also found in subjects exposed to the IH in recent studies [15,16,18,20], and our previous study also found that IH aggravates the tumor growth [23,31]. It is unclear what the potential molecular mechanism of IH accelerating tumor and the antioxidant effects on tumor-bearing mice exposed to the IH.…”